Process for the synthesis of ivabradine and addition salts thereof with a pharmaceutically acceptable acid

Abstract

Process for the synthesis of ivabradine of formula (I): addition salts thereof with a pharmaceutically acceptable acid, and hydrates thereof.

The invention claimed is: 
     
       1. A process for the synthesis of ivabradine of formula (I): 
       
         
           
           
               
               
           
         
         wherein a compound of formula (V): 
       
       
         
           
           
               
               
           
         
         is subjected to a reductive amination reaction with an amine of formula (VI): 
       
       
         
           
           
               
               
           
         
         in the presence of an iron-based catalyst, 
         optionally in the presence of trimethylamine N-oxide, 
         under dihydrogen pressure of from 1 to 20 bars, 
         in an organic solvent or mixture of organic solvents, 
         at a temperature from 25 to 100° C. 
       
     
     
       2. The process according to  claim 1 , wherein the iron-based catalyst has the following general formula: 
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3  and R 4  independently represent:
 a hydrogen atom, 
 an —SiR 5 R 6 R 7  group, wherein R 5 , R 6  and R 7  independently represent an optionally substituted, linear or branched (C 1 -C 6 )alkyl group or an optionally substituted aromatic or heteroaromatic group, 
 an optionally substituted aromatic or heteroaromatic group, 
 an optionally substituted, linear or branched (C 1 -C 6 )alkyl group, 
 an electron-attracting group, 
 an amine group that is aliphatic, aromatic, heteroaromatic or carrying an electron-attracting group, or 
 an aliphatic, aromatic or heteroaromatic ether group, 
 
         or the pairs R 1  and R 2 , or R 2  and R 3 , or R 3  and R 4 , together with the carbon atoms to which they are attached, form a 3- to 7-membered carbocycle or heterocycle, 
         X represents:
 an oxygen atom, 
 an —NH group or a nitrogen atom substituted by an aliphatic, aromatic, heteroaromatic or electron-attracting group, 
 a —PH group or a phosphorus atom substituted by one or more aliphatic, aromatic or electron-attracting groups, or 
 a sulphur atom, 
 
         L 1 , L 2  and L 3  independently represent a carbonyl, nitrile, isonitrile, heteroaromatic, phosphine, phosphite, phosphonite, phosphoramidite, phosphinite, phospholane, phospholene, aliphatic amine, aromatic amine, heteroaromatic amine, electron-attracting-group-carrying amine, aliphatic ether, aromatic ether, heteroaromatic ether, sulphone, sulphoxide or sulphoximine group or an N-heterocyclic carbene group having one of the two following formulae: 
       
       
         
           
           
               
               
           
         
         wherein Y and Z independently represent a sulphur or oxygen atom or an NR 8  group wherein R 8  represents an optionally substituted alkyl group or an optionally substituted aromatic or heteroaromatic group, 
         K represents a carbon or nitrogen atom, 
         R 9  and R 10  independently represent a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aromatic or heteroaromatic group, a halogen atom, an aliphatic, aromatic or heteroaromatic ether group, an aliphatic, aromatic or heteroaromatic amine group, or the pair R 9  and R 10 , together with the atoms to which they are attached, form a 3- to 7-membered carbocycle or heterocycle, 
         or 
       
       
         
           
           
               
               
           
         
         wherein R 11  and R 12  independently represent an optionally substituted alkyl group or an optionally substituted aromatic or heteroaromatic group and n is 1 or 2. 
       
     
     
       3. The process according to  claim 2 , wherein the iron-based catalyst has the following general formula: 
       
         
           
           
               
               
           
         
         wherein R 2  and R 3  each represent a hydrogen atom or, together with the carbon atoms to which they are attached, form a 3- to 7-membered carbocycle or heterocycle, 
         and R 1  and R 4  independently represent:
 an —SiR 5 R 6 R 7  group, wherein R 5 , R 6  and R 7  independently represent an optionally substituted, linear or branched (C 1 -C 6 )alkyl group or an optionally substituted aryl group, 
 an optionally substituted aromatic or heteroaromatic group, or 
 an optionally substituted, linear or branched (C 1 -C 6 )alkyl group. 
 
       
     
     
       4. The process according to  claim 3 , wherein the iron-based catalyst is selected from: 
       
         
           
           
               
               
           
         
       
     
     
       5. The process according to  claim 2 , wherein the iron-based catalyst has the following general formula: 
       
         
           
           
               
               
           
         
         wherein R 2  and R 3  each represent a hydrogen atom or, together with the carbon atoms to which they are attached, form a 3- to 7-membered carbocycle or heterocycle, 
         and R 1  and R 4  independently represent:
 an —SiR 5 R 6 R 7  group, wherein R 5 , R 6  and R 7  independently represent an optionally substituted, linear or branched (C 1 -C 6 )alkyl group or an optionally substituted aromatic or heteroaromatic group, 
 an optionally substituted aromatic or heteroaromatic group, or 
 an optionally substituted, linear or branched (C 1 -C 6 )alkyl group. 
 
       
     
     
       6. The process according to  claim 5 , wherein the iron-based catalyst is selected from: 
       
         
           
           
               
               
           
         
       
     
     
       7. The process according to  claim 2 , wherein the iron-based catalyst has the following formula: 
       
         
           
           
               
               
           
         
       
     
     
       8. The process according to  claim 2 , wherein the iron-based catalyst has the following formula: 
       
         
           
           
               
               
           
         
       
     
     
       9. The process according to  claim 1 , wherein the amount of catalyst used in the reductive amination reaction is from 1 mol % to 10 mol % relative to the aldehyde. 
     
     
       10. The process according to  claim 1 , wherein the amount of trimethylamine N-oxide used in the reductive amination reaction is from 0 to 3 equivalents relative to the catalyst. 
     
     
       11. The process according to  claim 10 , wherein the amount of trimethylamine N-oxide used in the reductive amination reaction is from 0.5 to 1.5 equivalents relative to the catalyst. 
     
     
       12. The process according to  claim 1 , wherein the dihydrogen pressure in the reductive amination reaction is from 1 to 10 bars. 
     
     
       13. The process according to  claim 1 , wherein the solvent in the reductive amination reaction is an alcohol. 
     
     
       14. The process according to  claim 13 , wherein the solvent in the reductive amination reaction is ethanol. 
     
     
       15. The process according to  claim 1 , wherein the temperature of the reductive amination reaction is from 50 to 100° C.